Alternative titles; symbols
SNOMEDCT: 307343001; ORPHA: 231401; DO: 0112125;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq21.1 | Alpha-thalassemia myelodysplasia syndrome, somatic | 300448 | 3 | ATRX | 300032 |
A number sign (#) is used with this entry because of evidence that alpha-thalassemia myelodysplasia syndrome (ATMDS) is caused in many cases by somatic mutation in the ATRX gene (300032) on chromosome Xq21.
The ATRX gene is also mutant in alpha-thalassemia/impaired intellectual development syndrome (301040) and in intellectual disability-hypotonic facies syndrome (309580).
Alpha-thalassemia is a common inherited form of anemia that usually results from deletion of 1 or more of the duplicated alpha-globin genes on chromosome 16 (Higgs et al., 1989). A mild form of alpha-thalassemia is also associated with a variety of developmental abnormalities in a rare, severe form of X-linked mental retardation (301040).
In the alpha-thalassemia myelodysplasia syndrome, alpha-thalassemia occurs as an acquired abnormality in association with a multilineage myelodysplasia. Gibbons et al. (2003) stated that 71 such individuals had been identified, of whom 62 (87%) were males who had a de novo, acquired form of alpha-thalassemia with hypochromic microcytic anemia. A reduction in alpha-globin expression leads to an excess of beta-globin chains, which form an abnormal hemoglobin, HbH (beta-4), which is readily detectable in peripheral blood.
Gibbons et al. (2003) demonstrated by gene expression studies using a microarray technique and RT-PCR that ATRX (300032) expression in granulocytes was 3 to 4% of that in normal controls.
Inherited mutations of specific genes have elucidated the normal roles of the proteins they encode by relating specific mutations to particular phenotypes. However, many potentially informative mutations in such genes are lethal early in development. Consequently, inherited mutations may not reflect all the functional roles of such proteins. Acquired, somatic defects reflect a wider spectrum of mutations because they are not prone to negative selection in development. It had been difficult to identify such mutations; microarray analysis provided a new opportunity to identify mutations and was the method used by Gibbons et al. (2003) in studying the relationship to the large (300 kb) ATRX gene in myelodysplasia associated with alpha-thalassemia (ATMDS). The ATRX gene encodes a member of the SWI2/SNF2 family of proteins. Like other members of this group, multiprotein complexes isolated by ATRX antibodies have ATP-dependent nucleosome-remodeling and DNA translocase activities in vitro. ATRX is a nuclear protein that localizes to nuclear subcompartments called PML bodies and to pericentromeric heterochromatin, where it interacts with a component of heterochromatin, HP1. Sequence analysis identified specific somatic mutations in the ATRX gene in granulocytes or bone marrow cells that were absent in buccal cells and a lymphoblastoid cell line.
Gibbons, R. J., Pellagatti, A., Garrick, D., Wood, W. G., Malik, N., Ayyub, H., Langford, C., Boultwood, J., Wainscoat, J. S., Higgs, D. R. Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS). Nature Genet. 34: 446-449, 2003. [PubMed: 12858175] [Full Text: https://doi.org/10.1038/ng1213]
Higgs, D. R., Vickers, M. A., Wilkie, A. O. M., Pretorius, I.-M., Jarman, A. P., Weatherall, D. J. A review of the molecular genetics of the human alpha-globin gene cluster. Blood 73: 1081-1104, 1989. [PubMed: 2649166]
Weatherall, D. J., Old, J., Longley, J., Wood, W. G., Clegg, J. B., Pollock, A., Lewis, M. J. Acquired haemoglobin H disease in leukemia: pathophysiology and molecular basis. Brit. J. Haemat. 38: 305-322, 1978. [PubMed: 273430] [Full Text: https://doi.org/10.1111/j.1365-2141.1978.tb01049.x]